Retinoic acid receptor activity in proximal tubules prevents kidney injury and fibrosis

Chronic kidney disease (CKD) is characterized by a gradual loss of kidney function and affects -13.4% of the global population. Progressive tubulointerstitial fibrosis, driven in part by proximal tubule (PT) damage, is a hallmark of late stages of CKD and contributes to the development of kidney failure, for which there are limited treatment options. Normal kidney development requires signaling by vitamin A (retinol), which is metabolized to retinoic acid (RA), an endogenous agonist for the RA receptors (RAR alpha, beta, gamma). RAR alpha levels are decreased in a mouse model of diabetic nephropathy and restored with RA administration; additionally, RA treatment reduced fibrosis. We developed a mouse model in which a spatiotemporal (tamoxifen- inducible) deletion of RAR alpha in kidney PT cells of adult mice causes mitochondrial dysfunction, massive PT injury, and apoptosis without the use of additional nephrotoxic substances. Long - term effects (3 to 4.5 mo) of RAR alpha deletion include increased PT secretion of transforming growth factor beta 1, inflammation, interstitial fibrosis, and decreased kidney function, all of which are major features of human CKD. Therefore, RAR alpha's actions in PTs are crucial for PT homeostasis, and loss of RAR alpha causes injury and a key CKD phenotype.